The pathogenesis of insulin requiring diabetes in man has been shown to have genetic (largely HLA associated) and autoimmune components, however the nature and timing of the caucasative events in the disease remains uncertain. In these proposals we undertake to utilize mouse models to explore chemical toxins to pancreatic beta cells as related to subsequent beta cell necrosis, inflammation of the islets and the diabetes state. In studies to date, we have shown that single "subdiabetogenic" doses of streptozotocin (SZ) in various strains of mice induce delayed onset hyperglycemia and inflammation of the islets over time. Sensitivity to the drug is increased in younger animals and in male versus female mice. Testosterone in vivo or in vitro augments the beta cell toxicity from SZ. These observations recall the early age of onset and the male to female preponderance of insulin requiring diabetes in man. The human incidence peak in early adolescence may also now have significance. Testosterone potentiation of SZ was at the level of the beta cell. There was a marked reduction in insulin containing cells compared to the changes induced by SZ alone, while glucagon containing cells migrated into the islet core and proliferated in number secondarily to the degree of beta cell necrosis. Phenobarbital pretreatments also augmented SZ induced beta cell necrosis suggesting that SZ may require enzymatic alteration for full potency. SZ also induced some antinuclear antibodies. Alloxan given to 3 week old male CDl mice at 240 mg/kg produced acute islet cell necrosis and diabetes. Alloxan at 220 mg/kg had transient effects while doses at less than 220 mg/kg had little effect. Alloxan did induce insulitis comparable to that seen with SZ however. Splenic transfers from SZ treated diabetic BALB/C nude heterozygous mice to untreated BALB/C nude homozygous mice failed to induce diabetes. Experiments are continuing to learn the relative role of induced autoimmunity in mice given single subdiabetogenic doses of SZ, alloxan, Vacor and L-asparaginase.